PROJECT SUMMARY The serious neurologic consequences of clinical vitamin B12 deficiency results is well-established, but it is generally believed that undiagnosed B12 deficiency is uncommon, present in approximately 5% of those aged ?60 y. There is also limited evidence that long-term, subclinical B12 deficiency, which is believed to be present in up to 40% of older individuals, leads to neurocognitive dysfunction. However, this relationship remains uncertain because of serious limitations in the existing evidence. Given its high prevalence, it is critical to understand the potential neurocognitive consequences of subclinical B12 deficiency. Many observational and clinical studies have suggested that subclinical B12 insufficiency is associated with reduced neurocognitive function in the elderly, but other studies have not. A major reason for these observed inconstancies is the difficulty in determining B12 status. Combining multiple measurements of B12 status, such as circulating B12, total homocysteine and methylmalonic acid, will provide a more reliable assessment of B12 status. Another key, but often overlooked, factor in the discrepancies between studies of B12 status and neurocognitive function is the failure to account for the worsening effect of excess folate on clinical effects of B12 insufficiency. Other limitations of existing studies of B12 and neurocognitive function that may be, in part, responsible for the inconsistent evidence are the lack of repeated assessment of B12 status during follow-up, insufficient numbers of subjects and follow-up duration, and heterogeneity and weaknesses in cognition-assessment methodology. Undertaking randomized trials to examine the relationship between subclinical B12 deficiency and cognitive decline is fraught with ethical considerations because it would require that individuals with low B12 levels go untreated for long periods of follow-up. Therefore, gaining a better understanding of inadequate vitamin B12 status in neurologic function of aging individuals will require well-designed observational studies. The goal of the proposed project is to address the critical gap in our understanding of B12 status and neurocognitive function using existing blood samples to assess folate status and B12 status using a combined marker based on the 3 aforementioned markers of B12 status, and existing data on cognitive decline, dementia including Alzheimer's disease, and brain atrophy in up to 3500 individuals followed for 20+ years. Existing samples and data from the Framingham Heart Study present a unique opportunity to assess the relationship between subclinical B12 deficiency and age-related neurocognitive changes with few limitations of earlier studies. Findings from the proposed study will provide a scientific basis for treatment of subclinical B12 deficiency and could have a substantial public health impact as subclinical deficiency of B12 is common and undiagnosed subclinical B12 deficiency may be an important missed opportunity for prevention of age-related neurocognitive decline and dementia. Subclinical B12 deficiency can be easily identified and treated with B12 supplements.